Murine Double Minute 2 SNP309 Research Articles

Association of rs1570360 and rs2010963 in VEGF and rs2279744 in the MDM2 gene with Recurrent Implantation Failure in Iranian Women.

The embryo implantation includes a complex sequence of signaling events, comprising numerous molecular mediators, such as ovarian hormones, cytokines, adhesion molecules and, growth factors. One of the critical factors in angiogenesis is the vascular endothelial growth factor (VEGF). The VEGF plays a pivotal role in embryonic development, decidua vascularization and placental angiogenesis. Furthermore, the P53 gene and its negative regulator, murine double minute 2 (MDM2), are major players in reproductive processes. This study aimed to assess the association of polymorphisms of the VEGF and the MDM2 genes with idiopathic recurrent implantation failure. We genotyped 60 women with previous idiopathic recurrent implantation failures and 60 fertile women as controls. Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing were used for genotyping the rs2010963 and the rs1570360 polymorphisms in VEGF; and the rs2279744 in MDM2 genes. Results indicated a higher frequency of the VEGF rs1570360 AA genotype and A allele in patients with a history of idiopathic implantation failure [OR=6.4 (1.22 - 33.64), p-value=0.02)]. However, the frequency of VEGF +405 G/C and MDM2 SNP309 T/G [(OR=3 (0.5 - 16) p-value=0.2, OR=1.18 (0.3 - 3.7) p-value=0.7, respectively)] genotypes were not significantly different between cases and controls. The VEGF polymorphism may influence embryo implantation and the VEGF rs1570360 AA genotype may predispose to the risk of recurrent implantation failure after IVF.

Association between TP53 and MDM2 Gene Polymorphisms and Risk of Hepatocellular Carcinoma in Hepatitis C Virus among Egyptian Populations

Background: The Murine double minute 2 (MDM2) gene is overexpressed in several human tumors. The oncogenic potential of MDM2 is partially explained by inhibition of the activity of the tumor suppressor protein P53 (negative regulator of the P53 tumor suppressor protein). A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene (T to G exchange at nucleotide 309) and TP53 gene (codon 72 exon 4, rs1042522 encoding either C or G) have been independently associated with increased risk of several cancer types. Few studies have analyzed the role of these polymorphisms in the development of hepatocellular carcinoma among Egyptian patients with chronic hepatitis C virus infection.
 Methods: The study consisted in the comparison of the genotype distribution of TP53 and MDM2 SNP309 in 100 viral hepatitis C-related hepatocellular carcinomas (HCC) cases and 100 controls without HCC matched for age, gender and ethnicity. PCR-RFLP (restriction fragment length polymorphism) and real time PCR methods were used to determine the genotype at the MDM2 SNP309T>G locus and TP53 rs1042522.
 Results: Overall, our results indicate that frequencies of TP53 alleles (C and G) were not significant different between HCC cases and healthy controls (p=0.093) (Odds Ratio, OR=1.361,95% Confidence Interval, 95% CI=0.949 – 1.951). A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among HCC cases (Odds Ratio, OR=4.868, 95% Confidence Interval, 95% CI= 2.873 – 8.251).
 Conclusions: Our finding suggest that people who have G allele increase the risk by 4.868 folds for developing HCC among Egyptian patients, consequently the MDM2 309T>G polymorphism is an important modulator of hepatocellular carcinoma development in Egyptian patients.

Single-Nucleotide Polymorphism 309T>G in the MDM2 Promoter Determines Functional Outcome After Stroke.

Background and Purpose- The E3 ubiquitin ligase MDM2 (murine double minute 2) is the main negative regulator of the p53 protein-a key player in neuronal apoptosis after ischemia. A functional single-nucleotide polymorphism in the human MDM2 gene promoter (rs2279744) regulates MDM2 protein expression. We investigated whether the MDM2 SNP309, by controlling p53-mediated apoptosis, determines functional outcome after stroke. Methods- Primary cortical neurons were subjected to oxygen and glucose deprivation. Mice were subjected to ischemic (transient middle cerebral artery occlusion) or hemorrhagic (collagenase injection) stroke models. Protein and mRNA levels of MDM2 and p53 were measured in both neuronal and brain extracts. The interaction of MDM2 with p53 was disrupted by neuronal treatment with nutlin-3a. siRNA was used to knockdown MDM2 expression. We analyzed the link between the MDM2 SNP309 and functional outcome, measured by the modified Rankin Scale scores, in 2 independent hospital-based stroke cohorts: ischemic stroke cohort (408 patients) and intracerebral hemorrhage cohort (128 patients). Results- Experimental stroke and oxygen and glucose deprivation induced the expression of MDM2 in the brain and neurons, respectively. Moreover, oxygen and glucose deprivation promoted MDM2 binding with p53 in neurons. Disruption of the MDM2-p53 interaction with nutlin-3a, or MDM2 knockdown by siRNA, triggered p53 accumulation, which increased neuronal susceptibility to oxygen and glucose deprivation-induced apoptosis. Finally, we showed that patients harboring the G allele in the MDM2 promoter had higher MDM2 protein levels and showed better functional outcome after stroke than those harboring the T/T genotype. The T/T genotype was also associated with large infarct volume in ischemic stroke and increased lesion volume in patients with intracerebral hemorrhage. Conclusions- Our results reveal a novel role for the MDM2-p53 interaction in neuronal apoptosis after ischemia and show that the MDM2 SNP309 determines the functional outcome of patients after stroke.

Murine Double Minute 2 SNP T309G Polymorphism and Urinary Tract Cancer Risk: A Meta-Analysis.

Urinary tract cancer is a common cause of cancer-related death. The etiology and pathogenesis of urinary tract cancer remain unclear, with genetic and epigenetic factors playing an important role. Studies of the polymorphism of murine double minute 2 (MDM2) have shown inconclusive trends in the risk of urinary tract cancer.To clarify this inconsistency, we conducted updated meta-analyses to evaluate the role of MDM2 T309G polymorphism in urinary tract cancer susceptibility.Data sources were Pubmed (1966–May 2015), Chinese biomedicine literature database (1978–May 2015), and hand searching of the reference lists of included studies:(1) research categories case-control study or a nested case-control study; (2) information evaluating the association between the MDM2 SNP309 and urinary tract cancer risk; (3) studies with sufficient data to perform a meta-analysis.It included the use of odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. We used I2 for the assessment of between-study heterogeneity, and publication bias was assessed using the funnel plot and the Egger test. Statistical analyses were performed by Review Manage, version 5.0 and Stata 11.0.A total of 18 studies met the eligibility criteria and were included in our analyses. Overall, there was no statistical association between MDM2 SNP309 and prostate cancer risk for the allele contrast, the GG genotype, the recessive genetic model, the dominant genetic model, and prostate cancer risk in all subjects (OR = 0.96, 95% CI 0.87–1.05, P = 0.36; OR = 0.93, 95% CI 0.75–1.15, P = 0.50; OR = 1.00, 95% CI 0.87–1.15, P = 0.99; OR = 0.93, 95% CI 0.80–1.07, P = 0.30), and between MDM2 SNP309 and bladder cancer risk (the allele contrast: OR = 1.06, 95% CI 0.89–1.27, P = 0.50; the GG genotype: OR = 1.12, 95% CI 0.79–1.61, P = 0.52; the dominant genetic model: OR = 1.03, 95% CI 0.83–1.28, P = 0.78; the recessive genetic model: OR = 1.12, 95% CI 0.84–1.49, P = 0.45). However, there was positive association between MDM2 SNP309 and kidney cancer risk for the allele contrast (OR = 1.24, 95% CI 1.05–1.46, P = 0.01), the GG genotype (OR = 1.57, 95% CI 1.11–2.20, P = 0.01), dominant model contrast (OR = 1.30, 95% CI 1.00–1.68, P = 0.05), the recessive genetic model (OR = 1.37, 95% CI 1.02–1.83, P = 0.04).First, only the data of published studies were included in this meta-analysis. Unpublished studies tend to show more negative results; therefore, publication bias may be present. Second, because of the lack of the original data, we did not perform stratification analysis by age, hormone levels, dietary habit, or other variables. This might have caused confounding bias. Third, because the number of studies was relatively small for kidney cancer, the results might not have enough statistical power for us to investigate the association of the polymorphism with kidney cancer susceptibility, and we could not perform subgroup analyses. Finally, there were no studies about Africans in this meta-analysis.In summary, the results of our meta-analysis suggest an increased risk role of the MDM2 SNP T309G in renal cancer. However, there was no association between the MDM2 SNP T309G and prostate cancer risk or between the MDM2 SNP T309G and bladder cancer risk. Moreover, well-designed studies should estimate different ethnicities, degree of malignancy and clinical progression on the association between MDM2 SNP309 and urinary cancer risk in the future.

Is MDM2 SNP309 Variation a Risk Factor for Head and Neck Carcinoma?

Murine double minute-2 (MDM2) is a negative regulator of P53, and its T309G polymorphism has been suggested as a risk factor for a variety of cancers. Increasing evidence has shown the association of MDM2 T309G polymorphism with head and neck carcinoma (HNC) risk. However, the results are inconsistent. Thus, we performed a meta-analysis to elucidate the association.The meta-analysis retrieved studies published up to August 2015, and essential information was extracted for analysis. Separate analyses on ethnicity, source of controls, sample size, detection method, and cancer types were also conducted. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to estimate the association.Pooled data from 16 case–control studies including 4625 cases and 6927 controls failed to indicate a significant association. However, in the subgroup analysis of sample sizes, an increased risk was observed in the largest sample size group (>1000) under a recessive model (OR = 1.52; 95% CI = 1.08–2.13). Increased risks were also found in the nasopharyngeal cancer in the subgroup analysis of cancer types (GG vs TT: OR = 2.07; 95% CI = 1.38–3.12; dominant model: OR = 1.48; 95% CI = 1.13–1.93; recessive model: OR = 1.76; 95% CI = 1.17–2.65).The results suggest that homozygote GG alleles of MDM2 SNP309 may be a low-penetrant risk factor for HNC, and G allele may confer nasopharyngeal cancer susceptibility.

TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes.

P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome.

AB065. MDM2 SNP309 polymorphism and lung cancer risk

Lung cancer is the most common type of cancer with high incidence rate and leading cancer cause death worldwide. Murine double minute 2 (MDM2) SNP309 polymorphisms have been reported to influence the risk of lung cancer. This study was conducted to determine the associate of the MDM2 SNP309 polymorphisms and lung cancer risk. One hundred and fifty patients were diagnosed with lung cancer in Respiratory Center, Nuclear Medicine and Oncology Center-BachMai Hospital and 173 controls who were selected to analyze clinical features and MDM2-SNP309 associated with lung cancer risk. The 309 GG genotype was associated with increased lung cancer risk in recessive model (OR =1.82; 95% CI, 1.09-3.05; P=0.02).

Effects of MDM2 promoter polymorphisms on the development of cervical neoplasia in a Southeastern Brazilian population

We investigated the importance of two adjacent functional polymorphisms in the Murine Double Minute 2 (MDM2) gene, SNP285 G > C and SNP309 T > G, for the development of cervical lesions in a Southeastern Brazilian population (293 cases and 184 controls). MDM2 genotyping was performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and/or DNA sequencing. MDM2 SNP309 has potential as a biomarker of cervical neoplasia in non-smokers, patients with family history of cancer, or those who had late sexual debut (>16 years). Besides, this polymorphism may help identify women at risk of developing severe cervical lesion at a young age (<30 years).

The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma.

The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.

MDM2 SNP309 polymorphism is associated with colorectal cancer risk.

The human murine double minute 2 (MDM2) is known as an oncoprotein through inhibiting P53 transcriptional activity and mediating P53 ubiquitination. Therefore, the amplification of MDM2 may attenuate the P53 pathway and promote tumorigenesis. The SNP309 T>G polymorphism (rs2279744), which is located in the intronic promoter of MDM2 gene, was reported to contribute to the increased level of MDM2 protein. In this hospital-based case-control study, which consisted of 573 cases and 588 controls, we evaluated the association between MDM2 SNP309 and the risk of colorectal cancer (CRC) in a Chinese population by using the TaqMan method to genotype the polymorphism. We found that the MDM2 SNP309 polymorphism was significantly associated with CRC risk. In addition, in our meta-analysis, we found a significant association between MDM2 SNP309 and CRC risk among Asians, which was consistent with our results. In conclusion, we demonstrated that the MDM2 SNP309 polymorphism increased the susceptibility of CRC in Asian populations.

MDM2 SNP309 is an ethnicity-dependent risk factor for digestive tract cancers

Published data on the relationship between T309G polymorphism in the murine double minute 2 (MDM2) gene and susceptibility of digestive tract cancers (DTC) are inconclusive. Thus, the aim of this study is to determine whether MDM2 T309G polymorphism is associated with the risk of diverse DTC, including esophagus, stomach, liver, bile duct, pancreas, and colorectum cancers. Relevant studies were identified up to October 1, 2013. Crude odds ratio (OR) and 95% confidence interval (CI) were used as a measure of the strength of the association. The pooled result based on all studies showed that there was a statistically significant link between MDM2 T309G polymorphism and DTC susceptibility (T vs. G: OR = 0.82, 95%CI = 0.76-0.88). When stratified by race, significant associations were observed for all genetic models among Asians (especially in Chinese population), but not among Caucasians. Subgroup analyses according to tumor location indicated that the genetic variant was associated with esophageal (OR = 0.88, 95%CI = 0.81-0.96 for T vs. G), hepatocellular (OR = 0.69, 95%CI = 0.57-0.84 for T vs. G) and pancreatic cancer risk but not associated with cholangiocarcinoma or colorectum cancer susceptibility. Meanwhile, the G allele was also suggested to be associated with increased gastric cancer risk (OR = 0.68, 95%CI = 0.54-0.87 for TT + TG vs. GG for intestinal type of gastric cancer and OR = 0.18, 95%CI = 0.06-0.50 for TT vs. GG for Helicobacter pylori infection positive stomach cancer). Our study indicates that the MDM2 T309G polymorphism may be an ethnicity-dependent risk factor for DTC, especially for the upper gastrointestinal tract malignancies.

Meta-analysis of associations between MDM2 SNP309 polymorphism and gastric cancer risk

Epidemiological studies have been conducted to evaluate genetic variations of murine double minute 2 (MDM2) SNP309 associated with the risk of gastric cancer (GC), although evidence remains conflicting. To gain a better understanding of this relationship, a meta-analysis was performed. Several electronic databases were searched up to February 2013, in order to identify relevant case-control studies. Seven published case-control studies with 2,199 cases and 3,201 controls were included. In the overall analysis, significant associations between the MDM2 SNP309 variant and GC risk were found for G vs. T alleles (OR=1.35; 95% CI, 1.24-1.47), GG vs. TT (OR=1.88; 95% CI, 1.59-2.24), recessive model (OR=1.71; 95% CI, 1.49-1.96). Furthermore, stratified by cancer site, significant associations were observed in gastric cardia cancer for all the models, although no significant association was found in any of the models among non-gastric cardia cancer, with the exception of the recessive model. In the subgroup analysis by source of control, MDM2 SNP309 was associated with increased GC risk for the hospital-based case-control (HCC) study for the GG vs. TT, recessive model and for the population-based case-control (PCC) study for the GG vs. TT, recessive model. Following stratification by gender and infection status of Helicobacter pylori (HP) for the recessive model, a significant association was found only in the HP-positive infected individuals. However, no statistically significant association was observed in males, females or the HP-negative infected individuals. In summary, the association between MDM2 SNP309 and GC risk was statistically significant, particularly in gastric cardia cancer for the HP-positive population group.

Polymorphisms in the MDM2 gene and risk of malignant bone tumors: a meta-analysis

There are several studies published to assess the associations of murine double minute 2 (MDM2) genetic polymorphisms with risk of malignant bone tumors, but they reported contradictory results and failed to confirm a strong and consistent association. To assess the evidence regarding the associations of MDM2 genetic polymorphisms with the risk of malignant bone tumors, we conducted a meta-analysis of epidemiological studies. The pooled odds ratio (OR) with its 95% confidence intervals (95% CI) was used to assess these possible associations. Four studies with a total of 3,958 individuals were finally included the meta-analysis. Meta-analysis of two studies on MDM2 SNP309 polymorphism showed that MDM2 SNP309 polymorphism was associated with an increased risk of malignant bone tumors (G versus T: OR = 1.72, 95% CI 1.35-2.20, P < 0.001; GG versus TT: OR = 2.64, 95% CI 1.59-4.39, P < 0.001; GG/GT versus TT: OR = 1.87, 95% CI 1.33-2.62, P < 0.001; GG versus TT/GT: OR = 2.20, 95% CI 1.38-3.51, P = 0.001). Meta-analysis of those two studies on MDM2 rs1690916 polymorphism showed that MDM2 rs1690916 minor allele A was associated with decreased risk of malignant bone tumors (OR = 0.60, 95% CI 0.46-0.77, P < 0.001). Meta-analyses of available data show that there are significant associations of MDM2 SNP309 polymorphism and MDM2 rs1690916 polymorphism with malignant bone tumors.

Relationship Between MDM2 and p53 Alterations in Colorectal Cancer and Their Involvement and Prognostic Value in the Tunisian Population

The prevalence of p53 mutations in colorectal cancer could reach 90%. The most important regulator of this protein that was identified originally was the Murine Double Minute2 (MDM2) oncoprotein, by which the levels of p53 were fixed through an autoregulatory feedback loop. In cancer cases, the overexpression of MDM2 deregulates this feedback, and the signaling pathway between MDM2 and p53 is blocked. We genotyped 167 patients and 167 healthy blood donors to determinate the mutational status of MDM2 and p53. Immunohistochemical analysis was performed on tumor and normal mucosa. The MDM2 polymorphism study showed a higher distribution of MDM2 SNP309 in tumors compared with healthy controls. At the same time, the majority of samples with SNP309 indicated a positive expression of MDM2 protein in the tumor. In this case, we found a first significant association between p53 expression and the single-strand conformational polymorphism analysis and a second association between the MDM2 polymorphism and p53 mutation. Moreover, the nuclear overexpression of MDM2 and SNP309 was significantly related to a higher mortality rate. In this work we wanted to highlight the role, which is becoming increasingly important, of MDM2. In fact, we conclude that the effects of MDM2 SNP309 may be considered a valuable prognostic marker to predict poor outcome for Tunisian patients with colorectal cancer.

Association of MDM2 SNP309 and TP53 Arg72Pro polymorphisms with risk of endometrial cancer

The incidence of endometrial cancer, a common gynecological malignancy, is increasing in Japan. We have previously shown that the ER/MDM2/p53/p21 pathway plays an important role in endometrial carcinogenesis. In the present study, we investigated the effects of germline single nucleotide polymorphisms in murine double minute 2 (MDM2) SNP309, TP53 Arg72Pro, ESR1 PvuII and XbaI, and p21 codon 31 on endometrial cancer risk. We evaluated these polymorphisms in DNA samples from 125 endometrial cancer cases and 200 controls using polymerase chain reaction-based restriction fragment length polymorphism. The association of each genetic polymorphism with endometrial cancer was examined by the odds ratio and 95% confidence interval, which were obtained using logistic regression analysis. The SNP309 GG genotype non-significantly increased the risk of endometrial cancer. The 95% confidence interval for the GG genotype vs. the TT genotype of MDM2 SNP309 was 1.76 (0.93–3.30). Endometrial cancer was not associated with tested SNP genotypes for TP53, ESR1 and p21. The combination of SNP309 GG + TG and TP53 codon 72 Arg/Arg significantly increased endometrial cancer risk. The adjusted OR was 2.53 (95% confidence interval, 1.03–6.21) and P for the interaction was 0.04. This result was supported by in vitro data showing that endometrial cancer cell lines with the SNP309 G allele failed to show growth inhibition by treatment with RITA, which reduces p53-MDM2 binding. The presence of the SNP309 G allele and TP53 codon 72 Arg/Arg genotype is associated with an increased risk of endometrial cancer in Japanese women.

Association ofMDM2andp53Polymorphisms with the Advancement of Cervical Carcinoma

Cervical cancer is one of the most common gynecological malignancies that causes a serious health problem worldwide. The aim of the present study was to analyze the association of p53 codon72 (arginine/proline) polymorphism (rs1042522) and Murine Double Minute 2 (MDM2) SNP309 T/G (rs2279744) with the advancement of cervical cancer by using polymerase chain reaction-restriction fragment length polymorphism method followed by direct sequencing. The frequencies of GG genotype at 309 position in the second promoter (P2) of MDM2 and Arginine in codon72 of p53 were found to be 3.5 (odds ratio [OR]=3.51; 95% confidence interval [CI]=1.93-6.4; p<0.0001) and 5 (OR=4.978; 95% CI=2.7-9.2; p<0.0001) fold higher, respectively, in cases than in the control. On gene-gene interactions between MDM2 and p53 polymorphisms, the frequency of MDM2 G/G and p53 Arg/Arg together was found to be 6.5-fold higher in cervical cancer patients compared with healthy controls (OR=6.497; 95% CI=2.987-14.13; p<0.0001). We found an association of p53 codon72 arginine and MDM2 SNP309 GG genotype with different clinical and histological grades, human papillomavirus (HPV) infection, and age at the time of diagnosis of cervical cancer. In conclusion, Arginine at codon72 of p53 and GG genotype at 309 in P2 of MDM2 together reveal a direct proportionality with the tumor grade of cervical cancer along with HPV infection in postmenopausal women.

MDM2 SNP309 polymorphism is associated with lung cancer risk in women: A meta-analysis using METAGEN.

Lung cancer is the most common diagnosed malignancy and the leading cause of cancer-related mortality worldwide. Murine double minute 2 (MDM2) SNP309 polymorphisms have been reported to influence the risk of lung cancer. However, the published studies together with four subsequent meta-analyses have yielded contradictory results. To examine this inconsistency, we conducted a meta-analysis of 6,696 lung cancer cases and 7,972 controls from eight published case-control studies using METAGEN. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with STATA software and used to assess the strength of the association. In the overall analysis, a significant association between MDM2 SNP309 polymorphism and lung cancer risk was observed (OR, 1.143; 95% CI, 1.047–1.247). Moreover, stratified by ethnicity, a significant association was found in Asians (OR, 1.260; 95% CI, 1.111–1.429), but not in Europeans. Subgroup analysis of gender, histology and smoking status suggested that the MDM2 SNP309 genotype was associated with increased lung cancer risk in women (OR, 1.282; 95% CI, 1.062–1.548) and never smokers (OR, 1.328; 95% CI, 1.119–1.575). No statistically significant association was observed in males and ever smoking population, and no association was found in subgroup analysis based on histology. In conclusion, the association between MDM2 SNP309 and lung cancer was statistically significant, particularly in Asians, women and never smoking population.

MDM2 SNP309 variation contributes to leukemia risk: meta-analyses based on 7259 subjects

Evidence implicates MDM2 (murine double minute-2) T309G polymorphism as a risk factor for several cancers. Increasing numbers of studies have been carried out on the association of MDM2 T309G polymorphism with susceptibility to leukemia and have generated conflicting results. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses assessing the association of MDM2 T309G variation with leukemia were conducted. Separate analyses on ethnicity and clinical types were also performed. Eligible studies were identified for the period up to February 2012. Consequently, seven publications including eight case–control studies with 1777 cases and 5482 controls were selected for analysis. The overall data indicated a significant association of the MDM2 T309G polymorphism with leukemia risk (GG vs. TT: odds ratio [OR] = 1.62; 95% confidence interval [CI] = 1.14–2.29; dominant model: OR = 1.20; 95% CI = 1.06–1.36; recessive model: OR = 1.47; 95% CI = 1.07–2.03). In subgroup analysis by ethnicity, the G allele may increase leukemia susceptibility among Asians (GG vs. TT: OR = 3.06; 95% CI = 2.05–4.56; dominant model: OR = 1.82; 95% CI = 1.31–2.51; recessive model: OR = 2.32; 95% CI = 1.69–3.19) but not Caucasians. In subgroup analysis by clinical types, data suggested increased risk for acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) under additive and recessive models, respectively. Similarly, elevated risk for chronic lymphocytic leukemia (CLL) was shown under the dominant model. Collectively, the results of the present study suggest that MDM2 T309G polymorphism might be a low-penetrant risk factor for leukemia among Asians but not Caucasians. The G allele might increase CLL susceptibility and homozygous GG might elevate AML and CML risk.

MDM2 SNP309T&gt;G polymorphism increases susceptibility to hepatitis B virus‐related hepatocellular carcinoma in a northeast Han Chinese population

The murine double minute 2 (MDM2) gene encodes a negative regulator of the tumour protein p53. A single nucleotide polymorphism (SNP) in MDM2 promoter, SNP309 T > G, has been showed to influence MDM2 protein expression and accelerate tumour formation. To investigate further the role of this locus, we examined the association of the SNP with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a northeast Han Chinese population. MDM2 SNP309 was genotyped in 310 HBV-related HCC patients, 314 non-HCC subjects with HBV infection and 480 healthy controls by using a PCR-RFLP method. Significant differences of MDM2 SNP309 were detected between HBV-related HCC patients and healthy controls (OR 1.729, 95%CI 1.369-2.183, P < 0.0001) or non-HCC subjects with HBV infection (OR 1.351, 95% CI 1.060-1.722, P = 0.015) by a logistic regression analysis. Our data also revealed that subjects with the G allele had higher HBV-related HCC susceptibility than those with the T allele in various genetic models. In a meta-analysis, where we pooled our data with other published studies, the association between this loci and the disease was further confirmed (pooled OR 1.54, 95% CI 1.37-1.72, P < 0.0001). These results suggested that the MDM2 SNP309 might influence the risk of developing HBV-related HCC in a northeast Han Chinese population.

Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck

Both p53 tumor suppressor and murine double minute 2 (MDM2) oncoprotein are crucial in carcinogenesis. We hypothesized that MDM2 promoter single nucleotide polymorphisms (SNPs) SNP309 T > G, A2164G, and p53 codon 72 are associated with risk and age at onset of squamous cell carcinoma of head and neck (SCCHN). We genotyped these SNPs in a study of 1,083 Caucasian SCCHN cases and 1,090 cancer-free controls. Although none of these SNPs individually had a significant effect on risk of SCCHN, nor did their combined putative risk genotypes (i.e., MDM2 SNP309 GT + GG, 2164 AA, and p53 codon 72 CC), we found that individuals with two to three risk genotypes had significantly increased risk of non-oropharyngeal cancer (OR = 1.42; 95% CI = 1.07-1.88). This increased risk was more pronounced among young subjects, men, smokers, and drinkers. In addition, female patients carrying the MDM2 SNP309 GT and GG genotypes showed a 3-yr (56.7 yr) and 9-yr (51.2 yr) earlier age at onset of non-oropharyngeal cancer (P(trend) = 0.007), respectively, compared with those carrying the TT genotype (60.1 yr). The youngest age (42.5 yr) at onset of non-oropharyngeal cancer was observed in female patients with the combined MDM2 SNP309 GG and p53 codon 72 CC genotypes. The findings suggest that MDM2 SNP309, A2164G, and p53 codon 72 SNPs may collectively contribute to non-oropharyngeal cancer risk and that MDM2 SNP309 individually or in combination with p53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. Further studies with large sample sizes are warranted to validate these results.